An endothelial-specific TIE2-L914F mouse model reveals cellular mechanisms of venous malformation progression and recapitulates the patient's response to targeted therapy

TIE2 p.L914F is the most common driver mutation of sporadic venous malformation (VM), a disease characterized by massively enlarged veins. The study of the molecular and cellular mechanisms contributing to TIE2-driven VM has been hindered by the lack of a genetic in vivo model. We generated a mouse system in which TIE2L914F is expressed postnatally in endothelial cells (EC). Mutant mice develop visible lesions with dilated veins with irregular smooth muscle cell coverage, histologically mimicking patients VM. With the use of an mCherry reporter we demonstrate that lesions form within the venous vasculature, and mutant ECs undergo clonal expansion fueled by a biphasic mechanism consisting of an early burst of proliferation followed by cell size increase. Targeted treatment with rapamycin partially reduces lesion growth by targeting increased proliferation and prolongs mouse survival, demonstrating this genetic murine model recapitulates the patients therapeutic response. Together, these findings provide new cellular and mechanistic insights into TIE2 p.L914F-driven venous malformation and establish a genetic platform for preclinical therapeutic studies.